DE10059418A1 - Ortho, meta-substituted bisaryl compounds, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them - Google Patents

Abstract

Compounds of the formula I, DOLLAR F1 in which A1 to A8, R (1), R (2), R (3), R (4), R (30) and R (31) have the meanings given in the claims very particularly suitable as novel antiarrhythmic agents, especially for the treatment and prophylaxis of atrial arrhythmias, e.g. B. atrial fibrillation (atrial fibrillation), AF) or atrial flutter (atrial flutter).

Description

The present invention relates to ortho, meta-substituted bisaryl compounds of the formula I,

in which mean:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another nitrogen, CH or CR5, at least four of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11), C (O) NR (12) R (13) or C (S) NR (12) R (13) ;
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2, 3 or 4,
where x cannot be 0 when R (14) is OR (15) or SO ₂ Me;
R (14) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (15), SO ₂ Me, phenyl naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl,
which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4,
where y cannot be 0 when R (16) is OR (17) or SO ₂ Me;
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7 , 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino.
R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16), where R (16) is as defined above;
z 0, 1, 2 or 3;
R (19) COOH, CONH ₂ , CONR (20) R (21), COOR (22) or CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF ₃ ;
or
R (3) and R (4)
together a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by -O-, -S-, -NH-, -N (methyl) - or -N (benzyl) -
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino, where in the event that several radicals A1 to A8 are CR (5), the radicals R (5) are defined independently of one another;
R (30) and R (31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R (30) and R (31)
together a chain of 2 methylene groups and their pharmaceutically acceptable salts.

Compounds of the formula I are preferred in which:
A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), at least 4 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2, 3 or 4,
where x cannot be 0 if R (14) is OR (15)
R (14) alkyl with 1, 2, 3, 4, C atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9 C atoms, CF ₃ , OR (15), phenyl, naphthyl, biphenylyl , Furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4;
where y cannot be 0 when R (16) is OR (17) or SO ₂ Me;
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, carbon atoms, CF ₃ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16), where R (16) is as defined above;
z 0, 1, 2 or 3;
R (19) CONH ₂ , CONR (20) R (21), COOR (22), CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH , Alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF ₃ ;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R (30) and R (31)
a chain of 2 methylene groups
as well as their pharmaceutically acceptable salts.

Compounds of the formula I are particularly preferred in which:
A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), with at most two of these groups A1-A8 being nitrogen and at least 4 of these groups being CH.

Also preferred are compounds of formula I in which:
A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), with at most two of these groups being nitrogen and at least 4 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x is 0, 1, 2, 3 or 4, where x cannot be 0 if R (14) is OR (15);
R (14) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (15), phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) hydrogen;
R (2) hydrogen, alkyl with 1, 2, 3 carbon atoms R (3);
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16);
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7 , 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
z 0, 1, 2 or 3;
R (19) CONH ₂ , CONR (20) R (21), COOR (22) or CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1 or 2 carbon atoms;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or methyl and their pharmaceutically acceptable salts.

Compounds of the formula I are very particularly preferred in which:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another nitrogen, CH or CR (5), at most one of these groups being nitrogen and at least 5 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13); R (9), R (10), R (11) and R (12)
independently of each other C _x H _2x -R (14);
x 0, 1, 2, 3 or 4;
R (14)
Alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) hydrogen;
R (2) is hydrogen or methyl;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4;
where y cannot be 0 when R (16) is OR (17);
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (4) is hydrogen, alkyl having 1 or 2 carbon atoms;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or methyl;
as well as their pharmaceutically acceptable salts

Compounds of the formula I in which:
A4 CH or nitrogen;
A1, A2, A3, A5, A6, A7 and A8
independently of one another CH or CR (5), at least 5 of these groups being CH.

Compounds of the formula I are very particularly preferred in which:
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2 or 3;
R (14) alkyl with 1, 2, 3 or 4, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9, carbon atoms, CF ₃ , phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , OH, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;
R (13) hydrogen;
R (2) hydrogen;
R (3) C _y H _2y -R (16),
y 0, 1 or 2;
R (16) alkyl with 1, 2, 3, C atoms, cycloalkyl with, 5 or 6 C atoms, CF ₃ , phenyl, or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF ₃ , alkyl with 1, 2 or 3 carbon atoms and alkoxy with 1, 2, carbon atoms;
R (4) hydrogen;
R (5) F, Cl, CF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2 or 3 C atoms or alkoxy with 1 or 2 C atoms;
R (30) and R (31)
independently of one another hydrogen or methyl;
as well as their pharmaceutically acceptable salts.

Compounds of the formula I in which:
R (1) C (O) OR (9) or COR (11);
R (9) and R (11)
independently of one another C _x H _2x -R (14);
x 0, 1, 2 or 3;
R (14) cycloalkyl with 5 or 6 carbon atoms or phenyl,
where phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , OH, alkyl with 1, 2, 3 C atoms or alkoxy with 1 or 2 C - atoms;
R (2) hydrogen
R (3) C _y H _2y -R (16);
y 0, 1 or 2;
R (16) alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1, 2 substituents selected from the group consisting of F, Cl, CF ₃ , OCF ₃ , alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;
R (4) hydrogen,
R (5) F, Cl, alkyl with 1, 2 or 3 C atoms or alkoxy with 1 or 2 C atoms;
R (30) and R (31)
Hydrogen;
as well as their pharmaceutically acceptable salts.

The invention also relates to the preparation of the compounds I and their use, especially in medicines.

The compounds according to the invention are not yet known. They act on the so-called Kv1.5 potassium channel and inhibit one as "Ultra-rapidly activating delayed rectifier" designated potassium current in the human atrium. The connections are therefore very special Suitable as novel antiarrhythmic agents, especially for Treatment and prophylaxis of atrial arrhythmias, e.g. B. Atrial Flicker (atrial fibrillation, AF) or atrial flutter (atrial flutter).

Atrial fibrillation (AF) and atrial flutter are the most common persistent ones Cardiac arrhythmias. The occurrence increases with age and leads often leading to fatal sequelae, such as a stroke. AF affects approximately 1 million Americans annually and leads to more than 80,000 Strokes every year in the US. The ones currently in use Class I and III antiarrhythmic drugs reduce the recurrence rate of AF, but find only because of their potential proarrhythmic side effects restricted use. Therefore, there is a high level of medical  Need to develop better medicines for treatment atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; "Newer developments in the management of atrial fibrillation ").

It has been shown that most supraventricular arrhythmias are subject to so-called "reentry" excitation waves. Such reentries occur when the heart tissue has a slow conductivity and at the same time very short refractory periods. Increasing the myocardial refractory period by extending the action potential is a recognized mechanism for ending arrhythmias or preventing their development (TJ Colatsky et al. Drug Dev. Res. 19, 1990, 129-140; "Potassium channels as targets for antiarrhythmic drug action "). The length of the action potential is essentially determined by the extent of repolarizing K ⁺ currents which flow out of the cell via various K ⁺ channels. Particularly important is the so-called "delayed rectifier" I _K , which consists of 3 different components: IK _r , IK _s and IK _ur .

Most known class III antiarrhythmics (e.g. dofetilide, E4031 and d-sotalol) block predominantly or exclusively the rapidly activating potassium channel IK _r , which can be detected both in cells of the human ventricle and in the atrium. However, it has been shown that these compounds have an increased proarrhythmic risk at low or normal heart rates, arrhythmias, in particular, which are referred to as "torsades de pointes" being observed (DM Roden, Am. J. Cardiol. 72, 1993, 44B-49B; "Current status of class III antiarrhythmic drug therapy"). In addition to this high, sometimes fatal risk at low frequency, the I _Kr blockers were found to have lost their effectiveness under the conditions of tachycardia in which the effect is needed ("negative use-dependence").

While some of these disadvantages may be overcome by blockers of the slow-activating component (IK _s ), their effectiveness has not been proven so far since no clinical studies with IK _s channel blockers are known.

The "particularly fast" activating and very slowly inactivating component of the delayed rectifier IK _ur (= ultra-rapidly activating delayed rectifier), which corresponds to the Kv1.5 channel, plays a particularly large role for the repolarization period in the human atrium. An inhibition of the IK _ur potassium outflow is therefore a particularly effective method for prolonging the atrial action potential and thus for ending or preventing atrial arrhythmias in comparison to the inhibition of IK _r or IK _s . Mathematical models of the human action potential suggest that the positive effect of a blockade of the IC _ur should be particularly pronounced especially under the pathological conditions of chronic atrial fibrillation (M. Courtemanche, RJ Ramirez, S. Nattel, Cardiovascular Research 1999, 42, 477-489: "Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model ").

In contrast to IK _r and IK _s , which also occur in the human ventricle, the IK _ur plays an important role in the human atrium, but not in the ventricle. For this reason, if the IK _ur flow is inhibited, in contrast to the blockage of IK _r or IK _s, the risk of a proarrhythmic effect on the ventricle is excluded from the outset. (Z. Wang et al. Circ. Res. 73, 1993, 1061-1076:
However, antiarrhythmics that act via a selective blockade of the IK _ur current or Kv1.5 channel are not yet available on the market. A blocking effect on the Kv1.5 channel has been described for numerous active pharmaceutical ingredients (e.g. Tedisamil, Bupivacaine or Sertindole), but the Kv1.5 blockade is only a side effect in addition to other main effects of the substances.

WO 98 04 521 and WO 99 37 607 claim aminoindanes and aminotetrahydronaphthalene as potassium channel blockers which block the Kv1.5 channel. Structurally related aminochromanes are also claimed as Kv1.5 blockers in WO 00 12 077. In the application WO 99 62 891 thiazolidinones are claimed which also block the potassium channel. The applications WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmics which are said to act by blocking the IK _ur . However, the same compounds were originally also described as immunosuppressants (WO 96 25 936). All the compounds described in the abovementioned applications are structurally completely different from the compounds according to the invention in this application. We do not know of any clinical data for any of the compounds claimed in the above applications.

It has now surprisingly been found that those described here ortho, meta-substituted biaryl compounds potent blockers of human Kv1.5 channels are. They can therefore be used as new types Antiarrhythmics with a particularly advantageous safety profile. In particular the compounds are suitable for the treatment of supraventricular arrhythmias, z. B. atrial fibrillation or atrial flutter.

The connections can be used to terminate existing atrial flicker or flutter to regain sinus Rhythm (cardioversion). In addition, the substances reduce the Susceptibility to new flicker events (preservation of the sinus Rhythm, prophylaxis).

The compounds according to the invention are not yet known.  

Some structurally related compounds that are not part of this invention are described in Synlett, 1994, 349 and Can. J. Chem. 2000; 905. The compounds A

have a carboxamide group in the ortho position to the second phenyl Ring on, and potassium channel blocking activity is not described.

According to the invention, alkyl radicals and alkylene radicals can be straight-chain or branched. This also applies to the alkylene radicals of the formulas C _x H _2x , C _y H _2y , C _z H _2z , C _v H _2v and C _w H _2w . Alkyl residues and alkylene residues can also be straight-chain or branched if they are substituted or contained in other residues, e.g. B. in an alkoxy radical or in a flourished alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, Nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl. The divalent residues derived from these residues, e.g. B. methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4- Butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc. are examples of alkylene radicals.

Cycloalkyl radicals can also be branched. Examples of cycloalkyl radicals with 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2- Methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl,  Cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4- Methylcyclohexyl, menthyl, cycloheptyl, cyclooctyl, etc.

N-containing heteroaromatics with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are considered especially 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3- Oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8- Cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8- Phthalazinyl. The corresponding N-oxides of these are also included Connections, e.g. B. 1-oxy-2-, 3- or 4-pyridyl.

The N-containing heterocycles pyrrolyl, imidazolyl, Quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Pyridyl represents both 2-, 3- and 4-pyridyl. Thienyl stands for 2- as well as 3-thienyl. Furyl stands for both 2- and 3-furyl.

Monosubstituted phenyl radicals can be in the 2-, 3- or 4-position be substituted, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- Position, trisubstituted in the 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5- Position. The same applies analogously to the N-containing ones Heteroaromatics, the thiophene or the furyl radical.

If a residue is substituted or trisubstituted, the substituents can be the same or  to be different.

When R (3) and R (4) together are a chain of 4 or b methylene groups mean, of which a methylene group replaced by -O-, -S-, -NH- etc. then these residues together with the nitrogen atom form the Formula I a 5 or 6-membered nitrogen heterocycle, such as. B. pyrrolidine, Piperidine, morpholine, thiomorpholine etc.

Contain the compounds of formula I one or more acidic or basic groups or one or more basic heterocycles, so include the corresponding physiological or toxicological compatible salts to the invention, in particular the pharmaceutical usable salts. So the compounds of formula I, the acidic Groups, e.g. B. wear one or more COOH groups, for example as Alkali metal salts, preferably white sodium or potassium salts, or as Alkaline earth metal salts, e.g. B. calcium or magnesium salts, or as Ammonium salts, e.g. B. as salts with ammonia or organic amines or amino acids can be used. Compounds of formula I, the one or more basic, i.e. H. protonatable, wear groups or one or containing several basic heterocyclic rings can also be in the form of their physiologically compatible acid addition salts with inorganic or organic acids are used, for example as hydrochlorides, Phosphates, sulfates, methanesulfonates, acetates, lactates, maleinates, fumarates, Malates, gluconates etc. contain the compounds of the formula I simultaneously acidic and basic groups in the molecule, in addition to those described Salt forms also inner salts, so-called betaines, to the invention. salts can be obtained from the compounds of the formula I by customary processes be, for example by combining with an acid or base in one Solvent or dispersant or by anion exchange other salts.  

With a corresponding substitution, the compounds of the formula I can be substituted into stereoisomeric forms are present. Contain the compounds of formula I. one or more asymmetry centers, so these can be independent each have the S configuration or the R configuration. to Invention include all possible stereoisomers, e.g. B. enantiomers or Diastereomers, and mixtures of two or more stereoisomeric forms, z. B. enantiomers and / or diastereomers, in any ratio. Enantiomers e.g. B. belong in enantiomerically pure form, both as left- as well as right-handed antipodes, and also in the form of mixtures of the two enantiomers in different ratios or in the form of Racemates to the invention. The production of individual stereoisomers can if desired by separating a mixture according to the usual Methods or z. B. done by stereoselective synthesis. If available of mobile hydrogen atoms, the present invention also encompasses all tautomeric forms of the compounds of formula I.

The compounds of formula I are different by chemical Methods can be produced, which also belong to the present invention. Some typical routes are shown in Schemes 1 through 4 below Reaction sequences outlined. A1 to A8 and the radicals R (1) to R (4), R (30) and R (31) are each defined as above, provided nothing else is specified below.

For example, a compound of formula I according to Scheme 1 is obtained (Method A) or Scheme 2 (Method B).  

Scheme 1

Bisaryls of the formula IV can be obtained by palladium-catalyzed Suzuki coupling (which can be carried out, for example, in the presence of Pd [(PPh ₃ )] ₄ as catalyst, sodium carbonate as base and 1,2-dimethoxyethane as solvent) of an aromatic halide of the formula III can be represented with an aromatic boronic acid of the formula II. If R (9) for an easily removable residue, such as. B. tert-butyl or benzyl, compounds Formei V can be obtained, which can then be converted into compounds of formula I by reaction with reagents R (1) -X and / or R (2) -Y.

The reactions of the compounds of formula V with compounds of Formula R (1) -X correspond to the known conversion of an amine into a Carboxamide, sulfonic acid, carbamate, urea or  Thiourea. The rest X stands for a suitable nucleofuge Leaving group, such as B. F, Cl, Br, imidazole, O-succinimide etc.

For the preparation of compounds of the formula I in which R (1) C (O) OR (9) means, i.e. carbamates, z. B. Compounds of formula R (1) -X where X is chlorine or O-succinimide, so Chloroformates or succinimidocarbonates.

For the preparation of compounds of the formula I in which R (1) is SO ₂ R (10), that is to say sulfonamides, compounds of the formula R (1) -X in which X is chlorine, that is to say sulfonic acid chlorides, are generally used.

For the preparation of compounds of the formula I in which R (1) COR (11) means, ie carboxamides, z. B. Compounds of formula R (1) -X used, where X is chlorine, imidazole or acetoxy, so Carboxylic acid chlorides, carboxylic acid imidazolides or mixed anhydrides. It but can also the free acids of formula R (1) -OH in the presence suitable condensing agents such as carbodiimides or TFFH used become.

For the preparation of compounds of the formula in which R (1) CONR (12) R (13) or C (S) NR (12) R (13) means ureas or thioureas, instead of the compounds of the formula R (1) -X, compounds of Formula R (12) N (= C = O), or R (12) N (= C = S), i.e. isocyanates or Thioisocyanates can be used.  

Scheme 2

Bisaryls of Formula VIII can be palladium-catalyzed Suzuki coupling an aromatic bromide, iodide or chloride of the formula VII with a aromatic boronic acid of the formula II are shown (Scheme 2). Hydrolysis of the esters with e.g. B LiOH gives the free acids of formula IX which by coupling with amines NHR (3) R (4) into the bisaryls of formula IV can be transferred. As described in Scheme 1, cleavage of the labile group R (9) compounds of formula V, which further become compounds Formula I can be implemented.

The abovementioned reactions of the compounds of the formulas IX with amines of the formula HNR (3) R (4) correspond to the known conversion of a carboxylic acid to a carboxamide. Numerous methods have been described in the literature for carrying out these reactions. They can be particularly advantageous by activating the carboxylic acid, e.g. B. with dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethyl carbodiimide hydrochloride (EDC) optionally with the addition of hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP). However, reactive acid derivatives can also first be synthesized by known methods, e.g. B. acid chlorides by reacting the carboxylic acids of formula IX or with inorganic acid halides, such as. B. SOCl ₂ , or acid imidazolides by reaction with carbonyldiimidazole, which are then, optionally with the addition of an auxiliary base, reacted with the amines of the formula HNR (3) R (4).

Scheme 3

The aromatic boronic acids of the formula II required in methods A and B can from the aromatics or aromatic halides of the formula XI by ortholithization or halogen-metal exchange followed by implementation with boric acid trimethyl ester (or other boric acid triesters) and subsequent acid hydrolysis can be synthesized.

Scheme 4

The halides of formula VII used in method B are according to literature known regulations can be synthesized or easily by common Esterification methods from the acids of the formula X known from the literature available. The aromatic ortho-haloamides used in method A. of formula III are according to scheme 4 from the esters of formula VII Hydrolysis to the acids X by coupling with amines NHR (3) R (4) available. The formation of the amide bond can be done on the above for the Implementation of compounds of formula IX to IV described ways respectively.

All procedures may be appropriate, some To temporarily protect the reaction steps of functional groups in the molecule. Such protection group techniques are familiar to the person skilled in the art. The selection a protective group for eligible groups and the procedures their introduction and splitting off are described in the literature and can if necessary, be adapted to the individual case without difficulty.

The compounds of the formula 1 according to the invention and their physiologically tolerable salts can be used on animals, preferably on mammals, and in particular on humans, as medicaments by themselves, in mixtures with one another or in the form of pharmaceutical preparations. The present invention also relates to the compounds of the formula I and their physiologically tolerable salts for use as medicaments, their use in the therapy and prophylaxis of the clinical pictures mentioned and their use for the manufacture of medicaments therefor and of medicaments with a K ⁺ channel-blocking action , The present invention furthermore relates to pharmaceutical preparations which, as an active ingredient, contain an effective dose of at least one compound of the formula I and / or a physiologically tolerable salt thereof, in addition to customary, pharmaceutically perfect excipients and auxiliaries. The pharmaceutical preparations normally contain 0.1 to 90 percent by weight of the compounds of the formula I and / or their physiologically tolerable salts. The pharmaceutical preparations can be prepared in a manner known per se. For this purpose, the compounds of the formula I and / or their physiologically tolerable salts together with one or more solid or liquid galenic carriers and / or auxiliaries and, if desired, in combination with other active pharmaceutical ingredients are brought into a suitable administration form or dosage form, which then as Medicines can be used in human medicine or veterinary medicine.

Medicaments, the compounds of formula I according to the invention and / or their contain physiologically acceptable salts, can be administered orally, parenterally, e.g. B administered intravenously, rectally, by inhalation or topically, the preferred application in individual cases, e.g. B. the respective appearance the disease to be treated.

Which excipients are suitable for the desired pharmaceutical formulation is familiar to the expert on the basis of his specialist knowledge. Next Solvents, gelling agents, suppository bases, tablet excipients and other active substance carriers can, for example, antioxidants, Dispersing agents, emulsifiers, defoamers, flavoring agents, Preservatives, solubilizers, means of achieving a Depot effect, buffer substances or dyes can be used.

The compounds of formula I can also be combined with other active pharmaceutical ingredients in order to achieve an advantageous therapeutic effect. In the treatment of cardiovascular diseases, advantageous combinations with cardiovascular active substances are possible. Such combination partners which are advantageous for cardiovascular diseases include, for example, other antiarrhythmics, such as class I, class II or class III antiarrhythmics, such as, for example, IK _s - or IK _r - channel blockers, for. B. dofetilide, or further antihypertensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K ⁺ channel activators, and alpha and beta receptor blockers, but also sympathomimetic and adrenergic compounds, and Na ⁺ / H ⁺ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotropic substances, such as. B. digitalis glycosides, or diuretics.

For an oral application, the active compounds with the suitable additives, such as carriers, stabilizers or inert Diluent, mixed and mixed in by the usual methods brought suitable dosage forms, such as tablets, coated tablets, Push-fit capsules, aqueous, alcoholic or oily solutions. As an inert carrier can e.g. B. gum arabic, magnesia, magnesium carbonate, Potassium phosphate, milk sugar, glucose or starch, especially corn starch, be used. The preparation can be both dry and done as wet granules. As an oily carrier or as a solvent For example, vegetable or animal oils come into consideration, such as Sunflower oil or cod liver oil. As a solvent for aqueous or alcoholic solutions come e.g. B. water, ethanol or sugar solutions or mixtures thereof. Other auxiliaries, also for others Application forms are e.g. B. polyethylene glycols and polypropylene glycols.

The active ones are used for subcutaneous or intravenous administration Compounds, if desired with the usual substances such as Solubilizers, emulsifiers or other auxiliaries, in solution, Bring suspension or emulsion. The compounds of formula I and their Physiologically acceptable salts can also be lyophilized and the obtained lyophilisates z. B. for the production of injection or Infusion preparations are used. As solvents such. B.  Water, physiological saline or alcohols, e.g. B. ethanol, Propanol, glycerol, also sugar solutions such as glucose or mannitol solutions, or mixtures of the different mentioned solvents.

As a pharmaceutical formulation for administration in the form of Aerosols or sprays are suitable e.g. B. solutions, suspensions or Emulsions of the active ingredients of the formula I or their physiologically tolerable Salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such Solvent. The wording can also be other, if necessary pharmaceutical excipients such as surfactants, emulsifiers and stabilizers and contain a propellant. Such a preparation contains the active ingredient usually in a concentration of about 0.1 to 10, in particular of about 0.3 to 3 percent by weight.

The dosage of the active ingredient to be administered of the formula I or physiologically acceptable salts of it depends on the individual case and is how usual for an optimal effect of the circumstances of the individual case adapt. So of course it depends on the frequency of administration and of the strength and duration of action of each for therapy or Prophylaxis used compounds, but also on the type and strength of the treating disease as well as gender, age, weight and individual responsiveness of the person or animal to be treated and whether acute or prophylactic therapy is used. Usually is the daily dose of a compound of formula I when administered to a patients weighing approximately 75 kg 0.001 mg / kg body weight to 100 mg / kg Body weight, preferably 0.01 mg / kg body weight to 20 mg / kg Body weight. The dose can be administered as a single dose or in several, e.g. B. two, three or four single doses. Especially in the treatment of acute cases of irregular heartbeat,  For example, in an intensive care unit, a parenteral can also be used Administration by injection or infusion, e.g. B. by intravenous Continuous infusion can be beneficial.

Experimental part List of abbreviations

Boc: tert-butyloxycarbonyl
DMAP: 4-dimethylaminopyridine
DCC: dicyclohexylcarbodiimide
DIPEA: N-ethyldiisopropylamine
DMAP: 4-dimethylaminopyridine
DME: 1,2-dimethoxyethane
EDC: N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride
Eq .: mole equivalent
HOBt: 1-hydroxy-1H-benzotriazole
Me: methyl
MeLi: methyl lithium (in hexane)
BuLi: butyllithium (in pentane)
RT: room temperature
RP-HPLC: reverse phase high performance chromatography
THF: tetrahydrofuran
TFFH: tetramethylfluoroamidinium hexafluorophosphate
TFA: trifluoroacetic acid

Synthesis of the boronic acids of formula II

The boronic acids were synthesized according to Scheme 3 - their synthesis is demonstrated using several examples:  

2- (tert-butoxycarbonylamino-methyl) phenylboronic acid

Connection 1

N-Boc-2-bromobenzylamine (5.72 g, 20 mmol) was dissolved in THF under argon, cooled to -78 ° C, treated with 13.75 ml MeLi (1.6 M in hexane, 22 mmol), after 1 h with 28 ml ( 1.5 M in pentane, 42 mmol) tert. BuLi was added and, after a further hour at -78 ° C., trimethyl borate (9.0 ml, 80 mmol) was added. After warming to room temperature, dilute hydrochloric acid to pH 6 was added, the mixture was extracted with dichloromethane, the organic phase was washed with saturated NaCl solution and dried. 5.1 g (100%) of a light yellow solid foam were obtained.
MS (FAB, sample with glycerin added): m / z = 308 (M + 57), 252 (M + 1).

(R) -2- (1-tert-butoxycarbonylaminoethyl) phenylboronic acid

Connection 2

2.2 g (10 mmol) of N-Boc- (R) -phenethylamine were dissolved in 50 ml of anhydrous THF, cooled to -78 ° C. and 14 ml (1.5 M solution in pentane, 21 mmol) of tert-butyllithium were added dropwise. The mixture was warmed to -20 ° C. over 2 h, then 4.5 ml (40 mmol) of trimethyl borate were added and the mixture was warmed to room temperature. The solution was cooled to 0 ° C., acidified to pH 6 with 10% HCl, the aqueous phase extracted with dichloromethane, the combined organic phases washed with saturated NaCl solution, dried and concentrated. 2.0 g (75%) of a light yellow solid foam were obtained which was used without further purification.
MS (FAB, sample with glycerin added): m / z = 322 (M + 57), 266 (M + 1).

3- (tert-Butoxycarbonylaminomethyl) pyridine-4-boronic acid

Connection 3

5.5 g (26.4 mmol) of N-Boc-3-aminomethylpyridine were dissolved in THF -78 ° C cooled, with 37 ml tert. BuLi (1.5 M in pentane, 55.5 mmol) was added and the deep green mixture slowly warmed to -20 ° C. After adding Trimethyl borate (12 ml, 105.6 mmol) was brought to room temperature warmed and stirred overnight. After adding dilute hydrochloric acid to pH 6, the solution was concentrated on a rotary evaporator and with Chloroform / isopropanol (3/1) extracted. The organic phase was dried and concentrated. 4.3 g (65%) of an orange solid were obtained which was used without further cleaning. MS (FAB, sample with glycerin offset): m / z 309 (M + 57).

Synthesis of aromatic halides of the formulas III and VII General procedure for the synthesis of the compounds of the formula VII with thionyl chloride

2.5 mmol of acid of the formula X are refluxed with 3 ml of thionyl chloride for 4 h and then concentrated. The crude reaction product is coevaporated twice with toluene, taken up in 12.5 ml of dichloromethane and mixed with 3 mmol of the amine NHR (3) R (4) and 5.5 mmol of triethylamine. The mixture is stirred overnight, washed with NaHCO ₃ solution, dried and concentrated. 1.5 to 2.5 mmol of the desired amide III are obtained, which can be used without further purification.

Examples of amides III according to general working instructions

The esters VII were synthesized according to regulations known from the literature, partly from the acids X by esterification according to standard laboratory procedures manufactured.

Example of ester halide VII

Construction of the biaryls by palladium-catalyzed Suzuki coupling to the Compounds of formulas IV (Scheme 1) and VIII (Scheme 2) General working instructions

To argon-gassed 1,2-dimethoxyethane (10 ml / mmol bromide III or VII) were 0.05 eq. Tetrakis triphenylphosphine palladium and 1 eq. of corresponding bromide III or VII added. After 10 min, 1.5 eq. added the corresponding boronic acid and lastly 2 eq. a 2 molar Sodium carbonate solution. The mixture was heated to reflux under argon for 18 h, cooled and diluted with methylene chloride. The mixture was water and saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography. When cleaning by RP-HPLC basic compounds were isolated as trifluoroacetates.  

Examples of bisaryls of the formula VIII

6- [2- (tert-Butoxycarbonylaminonnethyl) phenyl] pyridine-2-carboxylate

Connection 13

83 ml of 1,2-dimethoxyethane were gassed with argon, 481 mg (0.41 mmol) of Pd (PPh ₃ ) ₄ and 1.9 g (8.3 mmol) of 6-bromopicolinic acid ethyl ester were added. After 10 min, 3.16 g (12.5 mmol) of 2- (tert-butoxycarbonylamino-methyl) phenylboronic acid and finally 8.3 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 18 hours, after cooling it was diluted with dichloromethane and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 2.12 g (72%) of a viscous orange oil were obtained.
MS (Es +): m / z = 357 (M + 1).
¹ H NMR (CDCl ₃ ): δ = 8.13 (1H, dd, J = 7.7, 1.1 Hz); 7.96 (1H, t, J = 7.7 Hz); 7.77 (1H, dd, J = 7.7, 1.1 Hz); 7.74 (1H, d, J = 7.7 Hz); 7.52-7.38 (3H, m); 7.04 (1H, m); 4.54 (2H, q, J = 7.0 Hz); 4.22 (2H, m); 1.46 (9H, s); 1.44 (3H, t, J = 7.0 Hz).

Examples of bisaryls of the formula IV (according to method A)

In accordance with the general working procedure given above, the following compounds were synthesized, which are also examples:

Hydrolysis of biaryls VIII to the acids of formula IX (Scheme 2) General working instructions

1 eq. of the ester VIII was dissolved in methanol / THF (3/1, 5 ml / mmol) and with 2 eq. a 1 molar LiOH solution was added and the mixture was stirred at room temperature overnight. The solution was then diluted with water and adjusted to pH 3-4 with KHSO ₄ solution. It was extracted several times with dichloromethane, the organic phase was dried and concentrated. Yields between 90 and 95% are typically obtained.

The following compound of the formula IX was prepared in accordance with this specification:

Synthesis of amides IV by amide coupling with acids IX (Scheme 2) General working instructions for the amide coupling

1 eq. Acid IX is dissolved in dichloromethane (20 ml / mmol) and with 2 eq. triethylamine, 1.2 eq. EDC, 0.2 eq. DMAP and 1.2 eq. of the corresponding amine NH (R3) (R4) added and stirred overnight at room temperature. The reaction solution was washed with water and purified by RP-HPLC. Basic compounds were made isolated as trifluoroacetates.

According to this regulation, several examples were synthesized:

Elimination of the Boc protective group to give the amines V (Schemes 1 and 2) General working instructions

1 eq. the N-Boc compound is dissolved in dichloromethane / trifluoroacetic acid (3/1, 10 ml / mmol) dissolved and stirred at room temperature for 3 h. Then on The rotary evaporator was concentrated and coevaporated with toluene. The amines V. used for further implementations without further purification. All connections were characterized by mass spectrometry.

Implementation of the amines V with various reagents Compounds I according to the invention General working instructions for the conversion to carbamates of the formula I.

1 eq. of the amine V is dissolved in dichloromethane (approx. 10 ml / mmol) and with 1.2 eq. (2.2 eq. When using the trifluoroacetate) triethylamine and 1.2 eq. of succinimidyl carbonate (or optionally the corresponding chloroformate) are added and the mixture is stirred overnight. It is diluted with dichloromethane and washed with NaHCO ₃ solution. The organic phase is dried, concentrated and, if necessary, purified by RP-HPLC.

Example 12

{2- [6- (2-Pyridin-2-yl-ethylcarbamoyl) pyridin-2-yl] benzyl} carbamic acid (S) -1- (phenylethyl) ester

20 mg (0.06 mmol) of 6- (2-aminomethylphenyl) pyridine-2-carboxylic acid (2-pyridin-2-yl-ethyl) -amide were dissolved in 3 ml of dry dichloromethane, with 7 mg (0.07 mmol) of triethylamine and 18 mg (0.17 mmol) (S) -2-phenylethyloxycarbonyloxysuccinimide added. After a reaction time of 18 h, the mixture was diluted with 15 ml of dichloromethane, washed with saturated NaHCO ₃ solution and the organic phase was dried and concentrated. After cleaning by RP-HPLC, 12 mg (28%) of a colorless substance was obtained in the form of its bis (trifluoroacetate).
MS (Es +): m / z 481 (M + 1).
¹ H-NMR (CDCl ₃ ): δ = 8.60 (1H, m), 8.05-7.86 (3H, m), 7.58-7.29 (13H, m), 5.75 (1H, q, J = 6.6 Hz), 5.65 ( 1H, br s), 4.22 (2H, m), 3.93 (2H, t, J = 4.9 Hz), 3.84 (2H, m), 1.48 (3H, d, J = 6.6 Hz).

Other examples that were presented in accordance with the working instructions:

General working instructions for the conversion to amides of formula I.

• A) 1 eq. of the amine V is dissolved in dichloromethane (approx. 10 ml / mmol), with 1.2 eq. (2.2 eq. When using the trifluoroacetate) diisopropylethylamine and 1.2 eq. of acid chloride added and stirred overnight. It is diluted with dichloromethane and washed with NaHCO ₃ solution. The organic phase is dried, concentrated and, if necessary, purified by RP-HPLC.
• B) 1 eq. of the amine V is dissolved in dichloromethane (approx. 10 ml / mmol), with 1.2 eq (2.2 eq. when using the trifluoroacetate) diisopropylethylamine, with 1.2 eq. the acid and 1.2 eq. TFFH added and stirred overnight. It is diluted with dichloromethane and washed with NaHCO ₃ solution. The organic phase is dried, concentrated and, if necessary, purified by RP-HPLC.

Example 20

6- (2 - {[2- (4-methoxyphenyl) acetylamino] methyl} phenyl) pyridine-2-carboxylic acid (4-methoxyphenyl) amide

39 mg (0.12 mmol) were dissolved in 3 ml dichloromethane, 27 ml (0.144 mmol) 4-methoxyphenylacetyl chloride and 19 mg (0.144 mmol) DIPEA were added and the mixture was stirred overnight. It was diluted with 20 ml dichloromethane and washed with NaHCO ₃ solution. The organic phase was dried, concentrated and purified by RP-HPLC. 56 mg (78%) of the compound from Example 20 were isolated in the form of its trifluoroacetate.
MS (Es +): m / z = 482 (M + 1)
¹ H-NMR (CDCl3): δ = 9.77 (1H, br s), 8.23 (1H, d, J = 7.7 Hz), 7.94 (1H, t, J = 7.7 Hz), 7.54 (1H, d, J = 7.7 Hz), 7.45-7.36 and 7.09-6.76 (12H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (2H, s), 3.42 (2H, s).

Further examples according to general working instructions A or B

Pharmacological examinations

Human Kv1.5 channels were expressed in Xenopus oocytes. For this purpose, oocytes from Xenopus laevis were first isolated and defolliculated. Kvl.5 coding RNA synthesized in vitro was then injected into these oocytes. After 1-7 days of Kv1.5 protein expression, Kv1.5 currents were measured on the oocytes using the two-microelectrode voltage-clamp technique. The Kv1.5 channels were usually activated with 500 ms voltage jumps to 0 mV and 40 mV. The bath was flushed with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl ₂ 1.8 mM, MgCl ₂ 1 mM, HEPES 5 mM (titrated with NaOH to pH 7.4). These experiments were carried out at room temperature. The following were used for data collection and analysis: Geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D / A converter and software (ADInstruments, Castle Hill, Australia). The substances according to the invention were tested by adding them to the bath solution in different concentrations. The effects of the substances were calculated as the percentage inhibition of the Kv1.5 control current obtained when no substance was added to the solution. The data was then extrapolated using the Hill equation to determine the inhibitory concentrations IC ₅₀ for the respective substances.

The following IC ₅₀ values were determined in this way for the compounds listed below:

Claims (19)

1. Compounds of the formula I
in which mean:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another nitrogen, CH or CR5, at least four of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11), C (O) NR (12) R (13) or C (S) NR (12) R (13) ;
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2, 3 or 4,
where x cannot be 0 when R (14) is OR (15) or SO ₂ Me;
R (14) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (15), SO ₂ Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6 , 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl,
which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4,
where y cannot be 0 when R (16) is OR (17) or SO ₂ Me;
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7 , 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino.
R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16), where R (16) is as defined above;
z 0, 1, 2 or 3;
R (19) COOH, CONH ₂ , CONR (20) R (21), COOR (22) or CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF ₃ ;
or
R (3) and R (4)
together a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by -O-, -S-, -NH-, -N (methyl) - or -N (benzyl) -;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino, where in the event that several radicals A1 to A8 are CR (5), the radicals R (5) are defined independently of one another;
R (30) and R (31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R (30) and R (31)
together a chain of 2 methylene groups and their pharmaceutically acceptable salts. 2. Compounds of formula I according to claim 1, in which:
A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), at least 4 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2, 3 or 4,
where x cannot be 0 if R (14) is OR (15)
R (14) alkyl with 1, 2, 3, 4, C atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9 C atoms, CF ₃ , OR (15), phenyl, naphthyl, biphenylyl , Furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF ₃ ;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4;
where y cannot be 0 when R (16) is OR (17) or SO ₂ Me;
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, carbon atoms, CF ₃ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16), where R (16) is as defined above;
z 0, 1, 2 or 3;
R (19) CONH ₂ , CONR (20) R (21), COOR (22), CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH , Alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF ₃ ;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R (30) and R (31)
a chain of 2 methylene groups
as well as their pharmaceutically acceptable salts. 3. Compounds of formula I according to claim 2, characterized in that A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), where at most two of these groups A1-A8 are nitrogen and at least 4 of these groups mean CH. 4. Compounds of formula I according to claim 1, characterized in that mean:
A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), with at most two of these groups being nitrogen and at least 4 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2, 3 or 4,
where x cannot be 0 when R (14) is OR (15);
R (14) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (15), phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (15) alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF ₃ or phenyl which is unsubstituted or substituted with 1, 2 or 3 substituents from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) hydrogen;
R (2) hydrogen, alkyl with 1, 2, 3 carbon atoms R (3);
R (3) CHR (18) R (19);
R (18) is hydrogen or C _z H _2z -R (16);
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7 , 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
z 0, 1, 2 or 3;
R (19) CONH ₂ , CONR (20) R (21), COOR (22) or CH ₂ OH;
R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C _v H _2v - CF ₃ or C _w H _2w -phenyl,
wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (22) alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R (4) is hydrogen, alkyl having 1 or 2 carbon atoms;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or methyl and their pharmaceutically acceptable salts. 5. Compounds of formula I according to claims 1-3, characterized in that therein:
A1, A2, A3, A4, A5, A6, A7 and A8
independently of one another nitrogen, CH or CR (5), at most one of these groups being nitrogen and at least 5 of these groups being CH;
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of each other C _x H _2x -R (14);
x 0, 1, 2, 3 or 4;
R (14)
Alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (13) hydrogen;
R (2) is hydrogen or methyl;
R (3) C _y H _2y -R (16);
y 0, 1, 2, 3 or 4;
where y cannot be 0 when R (16) is OR (17);
R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR (17), SO ₂ Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (17) is hydrogen, alkyl of 1, 2; 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R (4) is hydrogen, alkyl having 1 or 2 carbon atoms;
R (5) F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R (30) and R (31)
independently of one another hydrogen or methyl;
as well as their pharmaceutically acceptable salts 6. Compounds of formula I according to claim 5, characterized in that therein:
A4 CH or nitrogen;
A1, A2, A3, A5, A6, A7 and A8
independently of one another CH or CR (5), at least 5 of these groups being CH. 7. Compounds of formula I according to claim 6, characterized in that therein:
R (1) C (O) OR (9), SO ₂ R (10), COR (11) or C (O) NR (12) R (13);
R (9), R (10), R (11) and R (12)
independently of one another C _x H _2x -R (14);
x 0, 1, 2 or 3;
R (14) alkyl with 1, 2, 3 or 4, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9, carbon atoms, CF ₃ , phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , OH, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;
R (13) hydrogen;
R (2) hydrogen;
R (3) C _y H _2y -R (16),
y 0, 1 or 2;
R (16) alkyl with 1, 2, 3, C atoms, cycloalkyl with, 5 or 6 C atoms, CF ₃ , phenyl, or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF ₃ , alkyl with 1, 2 or 3 carbon atoms and alkoxy with 1, 2, carbon atoms;
R (4) hydrogen;
R (5) F, Cl, CF ₃ , CN, COOMe, CONH ₂ , COMe; NH ₂ , OH, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;
R (30) and R (31)
independently of one another hydrogen or methyl. 8. Compounds of formula I according to claim 7, characterized in that therein:
R (1) C (O) OR (9) or COR (11);
R (9) and R (11)
independently of one another C _x H _2x -R (14);
x 0, 1, 2 or 3;
R (14) cycloalkyl with 5 or 6 carbon atoms or phenyl,
where phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , OH, alkyl with 1, 2, 3 C atoms or alkoxy with 1 or 2 C - atoms;
R (2) hydrogen
R (3) C _y H _2y -R (16);
y 0, 1 or 2;
R (16) alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted with 1, 2 substituents selected from the group consisting of F, Cl, CF ₃ , OCF ₃ , alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;
R (4) hydrogen,
R (5) F, Cl, alkyl with 1, 2 or 3 C atoms or alkoxy with 1 or 2 C atoms;
R (30) and R (31)
Hydrogen. 9. Compounds of formula I according to one or more of claims 1 to 8 and their pharmaceutically acceptable salts for use as Drug. 10. Pharmaceutical preparation containing an effective amount at least one compound of formula I according to one or more of the Claims 1 to 8 and / or a pharmaceutically acceptable salt thereof as an active ingredient, together with pharmaceutically acceptable carriers and Additives and possibly one or more others pharmacological agents. 11. Use of a compound of formula I according to one or more of claims 1 to 8 and / or a pharmaceutically acceptable salt thereof for the manufacture of a medicament with a K ⁺ channel blocking effect for the therapy and prophylaxis of K ⁺ channel mediated diseases. 12. Use of a compound of formula I according to one or more of claims 1 to 8 and / or a pharmaceutically acceptable salt of which for the manufacture of a medicament for the therapy or prophylaxis of Cardiac arrhythmia remedied by action potential extension  can be. 13. Use of a compound of formula I according to one or more of claims 1 to 8 and / or a pharmaceutically acceptable salt of which for the manufacture of a medicament for the therapy or prophylaxis of Reentry arrhythmias. 14. Use of a compound of formula I according to one or more of claims 1 to 8 and / or a pharmaceutically acceptable salt of which for the manufacture of a medicament for the therapy or prophylaxis of supraventricular arrhythmias. 15. Use of a compound of formula I according to one or more of claims 1 to 8 and / or a pharmaceutically acceptable salt of which for the manufacture of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter. 16. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt of which for the manufacture of a medicament for the termination of atrial Fibrillation or atrial flutter (cardioversion). 17. Pharmaceutical preparation containing an effective amount at least one compound of formula I according to one or more of the Claims 1 to 8 and / or a pharmaceutically acceptable salt thereof and an IKr channel blocker as active ingredients, together with pharmaceutical acceptable carriers and additives. 18. Pharmaceutical preparation containing an effective amount at least one compound of formula 1 according to one or more of the Claims 1 to 8 and / or a pharmaceutically acceptable salt thereof  and an IKs channel blocker as active ingredients, together with pharmaceutical acceptable carriers and additives. 19. Pharmaceutical preparation containing an effective amount at least one compound of formula I according to one or more of the Claims 1 to 8 and / or a pharmaceutically acceptable salt thereof as well as a beta blocker as active ingredients, together with pharmaceutical acceptable carriers and additives.